Algorithm Training and Testing for a Nonendoscopic Barrett's Esophagus Detection Test in Prospective Multicenter Cohorts.

BACKGROUND & AIMS: Endoscopic Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) detection is invasive and expensive. Nonendoscopic BE/EAC detection tools are guideline-endorsed alternatives. We previously described a 5-methylated DNA marker (MDM) panel assayed on encapsulated sponge cell collection device (CCD) specimens. We aimed to train a new algorithm using a 3-MDM panel and test its performance in an independent cohort. METHODS: Algorithm training and test samples were from 2 prospective multicenter cohorts. All BE cases had esophageal intestinal metaplasia (with or without dysplasia/EAC); control subjects had no endoscopic evidence of BE. The CCD procedure was followed by endoscopy. From CCD cell lysates, DNA was extracted, bisulfite treated, and MDMs were blindly assayed. The algorithm was set and locked using cross-validated logistic regression (training set) and its performance was assessed in an independent test set. RESULTS: Training (N = 352) and test (N = 125) set clinical characteristics were comparable. The final panel included 3 MDMs (NDRG4, VAV3, ZNF682). Overall sensitivity was 82% (95% CI, 68%-94%) at 90% (79%-98%) specificity and 88% (78%-94%) sensitivity at 84% (70%-93%) specificity in training and test sets, respectively. Sensitivity was 90% and 68% for all long- and short-segment BE, respectively. Sensitivity for BE with high-grade dysplasia and EAC was 100% in training and test sets. Overall sensitivity for nondysplastic BE was 82%. Areas under the receiver operating characteristic curves for BE detection were 0.92 and 0.94 in the training and test sets, respectively. CONCLUSIONS: A locked 3-MDM panel algorithm for BE/EAC detection using a nonendoscopic CCD demonstrated excellent sensitivity for high-risk BE cases in independent validation samples. (Clinical trials.gov: NCT02560623, NCT03060642.).

An Endoscopic Scoring System for Achalasia: The CARS score.

BACKGROUND AND AIMS: The diagnosis of achalasia is associated with an average delay of two years. Endoscopic features may prompt an earlier diagnosis. We aimed to develop and test a novel endoscopic CARS score for the prediction of achalasia. METHODS: Part 1: Twenty endoscopic videos were taken from patients undergoing endoscopy for dysphagia or reflux. A survey with videos and endoscopic criteria options was distributed to 6 esophagologists and 6 general gastroenterologists. Inter-rater reliability (IRR) was measured and logistic regression was used to evaluate predictive performance. Three rounds of review were conducted to select the final score of four components. PART 2: A retrospective review was conducted for consecutive patients who had comprehensive esophageal testing. Each patient had a CARS endoscopic score calculated based on findings reported at endoscopy. RESULTS: From a video review and analysis of score components, IRR ranged from 0.23 to 0.57 for score components. The final CARS score was selected based on the following four components: Contents, Anatomy, Resistance, and Stasis. In a mixed effects model, the mean score across raters was higher for achalasia compared to non-achalasia subjects (4.44 vs. 0.87, p = < 0.01). In part 2 of the study, achalasia patients had a higher mean CARS score compared to those with no / ineffective motility disorder (mean 4.1 vs 1.3, p = < 0.01). CONCLUSIONS: We developed a CARS score based on reliability performance in a video-based survey and tested the score in clinical setting. The CARS score performed well in predicting achalasia.

A Delphi Method for Development of a Barrett's Esophagus Question Prompt List as a Communication Tool for Optimal Patient-physician Communication.

BACKGROUND METHODS: The question prompt list content was derived through a modified Delphi process consisting of 3 rounds. In round 1, experts provided 5 answers to the prompts "What general questions should patients ask when given a new diagnosis of Barrett's esophagus" and "What questions do I not hear patients asking, but given my expertise, I believe they should be asking?" Questions were reviewed and categorized into themes. In round 2, experts rated questions on a 5-point Likert scale. In round 3, experts rerated questions modified or reduced after the previous rounds. Only questions rated as "essential" or "important" were included in Barrett's esophagus question prompt list (BE-QPL). To improve usability, questions were reduced to minimize redundancy and simplified to use language at an eighth-grade level (Fig. 1). RESULTS: Twenty-one esophageal medical and surgical experts participated in both rounds (91% males; median age 52 years). The expert panel comprised of 33% esophagologists, 24% foregut surgeons, and 24% advanced endoscopists, with a median of 15 years in clinical practice. Most (81%), worked in an academic tertiary referral hospital. In this 3-round Delphi technique, 220 questions were proposed in round 1, 122 (55.5%) were accepted into the BE-QPL and reduced down to 76 questions (round 2), and 67 questions (round 3). These 67 questions reached a Flesch Reading Ease of 68.8, interpreted as easily understood by 13 to 15 years olds. CONCLUSIONS: With multidisciplinary input, we have developed a physician-derived BE-QPL to optimize patient-physician communication. Future directions will seek patient feedback to distill the questions further to a smaller number and then assess their usability.

Interrater Reliability of Functional Lumen Imaging Probe Panometry and High-Resolution Manometry for the Assessment of Esophageal Motility Disorders.

INTRODUCTION: High-resolution manometry (HRM) and functional lumen imaging probe (FLIP) are primary and/or complementary diagnostic tools for the evaluation of esophageal motility. We aimed to assess the interrater agreement and accuracy of HRM and FLIP interpretations. METHODS: Esophageal motility specialists from multiple institutions completed the interpretation of 40 consecutive HRM and 40 FLIP studies. Interrater agreement was assessed using intraclass correlation coefficient (ICC) for continuous variables and Fleiss' κ statistics for nominal variables. Accuracies of rater interpretation were assessed using the consensus of 3 experienced raters as the reference standard. RESULTS: Fifteen raters completed the HRM and FLIP studies. An excellent interrater agreement was seen in supine median integral relaxation pressure (ICC 0.96, 95% confidence interval 0.95-0.98), and a good agreement was seen with the assessment of esophagogastric junction (EGJ) outflow, peristalsis, and assignment of a Chicago Classification version 4.0 diagnosis using HRM (κ = 0.71, 0.75, and 0.70, respectively). An excellent interrater agreement for EGJ distensibility index and maximum diameter (0.91 [0.90-0.94], 0.92 [0.89-0.95]) was seen, and a moderate-to-good agreement was seen in the assignment of EGJ opening classification, contractile response pattern, and motility classification (κ = 0.68, 0.56, and 0.59, respectively) on FLIP. Rater accuracy for Chicago Classification version 4.0 diagnosis on HRM was 82% (95% confidence interval 78%-84%) and for motility diagnosis on FLIP Panometry was 78% (95% confidence interval 72%-81%). DISCUSSION: Our study demonstrates high levels of interrater agreement and accuracy in the interpretation of HRM and FLIP metrics and moderate-to-high levels for motility classification in FLIP, supporting the use of these approaches for primary or complementary evaluation of esophageal motility disorders.

Real-world evidence of safety and effectiveness of Barrett's endoscopic therapy.

BACKGROUND AND AIMS: Real-world data on the adverse events and the survival benefit of Barrett's endoscopic therapy (BET) are limited. The aim of this study was to examine the safety and effectiveness (survival benefit) of BET in patients with neoplastic Barrett's esophagus (BE). METHODS: An electronic health record-based database (TriNetX) was used to select patients with BE with dysplasia and esophageal adenocarcinoma (EAC) from 2016 to 2020. Primary outcome was 3-year mortality among patients with high-grade dysplasia (HGD) or EAC who underwent BET versus 2 comparison cohorts: patients with HGD or EAC who had not undergone BET and patients with GERD but no BE/EAC. Secondary outcome was adverse events (esophageal perforation, upper GI bleeding, chest pain, and esophageal stricture) after BET. To control for confounding variables, 1:1 propensity score matching was performed. RESULTS: We identified 27,556 patients with BE and dysplasia, of whom 5295 underwent BET. After propensity score matching, patients with HGD and EAC who underwent BET had significantly lower 3-year mortality (HGD risk ratio [RR], .59; 95% CI, .49-.71; EAC RR, .53; 95% CI, .44-.65) compared with corresponding cohorts who did not undergo BET (P < .001). There was no difference in median 3-year mortality between control subjects (GERD without BE/EAC) compared with patients with HGD (RR, 1.04; 95% CI, .84-1.27) who underwent BET. Finally, there was no difference in median 3-year mortality between patients who underwent BET compared with patients who underwent esophagectomy among both HGD (RR, .67; 95% CI, .39-1.14; P =.14) and EAC (RR, .73; 95% CI, .47-1.13; P = .14). Esophageal stricture was the most common adverse event (6.5%) after BET. CONCLUSIONS: Real-world, population-based evidence from this large database shows that endoscopic therapy is safe and effective for patients with BE. Endoscopic therapy is associated with a significantly lower 3-year mortality; however, it leads to esophageal strictures in 6.5% of treated patients.

The broad impact of functional lumen imaging probe panometry in addition to high-resolution manometry in an esophageal clinical practice.

High-resolution manometry (HRM) with the Chicago Classification (CC) is the standard paradigm to define esophageal motility disorders. Functional lumen imaging probe (FLIP) panometry utilizes impedance planimetry to characterize esophageal compliance and secondary peristalsis. The aim of this study was to explore the clinical impact of FLIP panometry in addition to HRM. A retrospective chart review was performed on FLIP panometry cases utilizing the 322N catheter. Cases with prior foregut surgeries or botulinum injection within 6 months of FLIP panometry were excluded. EGJ-diameter and distensibility index (DI) and secondary contraction patterns at increasing balloon volumes were recorded. An EGJ-DI of ≥2.8 mm2/mm Hg at 60 mL was considered as a normal EGJ distensibility. CC diagnosis, Eckhardt score, Brief Esophageal Dysphagia Questionnaire, and clinical outcomes were obtained for each FLIP case. A total of 186 cases were included. Absent contractility and achalasia types 1 and 2 showed predominantly absent secondary contraction patterns, while type 3 had a variety of secondary contractile patterns on FLIP panometry. Among 77 cases with EGJ outflow obstruction (EGJOO), 60% had a low EGJ-DI. Among those with no motility disorder or ineffective esophageal motility on HRM, 27% had a low DI and 47% had sustained contractions on FLIP, raising concern for an esophageal dysmotility process along the achalasia and/or spastic spectrum. FLIP panometry often confirmed findings on HRM in achalasia and absent contractility. FLIP panometry is useful in characterizing EGJOO cases. Spastic features on FLIP panometry may raise concern for a motility disorder on the spastic spectrum not captured by HRM. Further studies are needed on FLIP panometry to determine how to proceed with discrepancy with HRM and explore diagnoses beyond the CC.

An Endoscopic and Histologic Study on Healing of Radiofrequency Ablation Wounds in Patients With Barrett's Esophagus.

INTRODUCTION: Radiofrequency ablation (RFA) of Barrett's esophagus (BE) inflicts a wound spanning 3 epithelial types (stratified squamous, Barrett's metaplasia, gastric epithelium), yet the esophageal injury heals almost completely with squamous epithelium. Knowledge of how this unique wound heals might elucidate mechanisms underlying esophageal metaplasia. We aimed to prospectively and systematically characterize the early endoscopic and histologic features of RFA wound healing. METHODS: Patients with nondysplastic BE had endoscopy with systematic esophageal photographic mapping, biopsy, and volumetric laser endomicroscopy performed before and at 1, 2, and 4 weeks after RFA. RESULTS: Seven patients (6 men; mean age 56.1 ± 10.9 years) completed this study. Squamous re-epithelialization of RFA wounds did not only progress exclusively through squamous cells extending from the proximal wound edge but also progressed through islands of squamous epithelium sprouting throughout the ablated segment. Volumetric laser endomicroscopy revealed significant post-RFA increases in subepithelial glandular structures associated with the squamous islands. In 2 patients, biopsies of such islands revealed newly forming squamous epithelium contiguous with immature-appearing squamous cells arising from esophageal submucosal gland ducts. Subsquamous intestinal metaplasia (SSIM) was found in biopsies at 2 and/or 4 weeks after RFA in 6 of 7 patients. DISCUSSION: RFA wounds in BE are re-epithelialized, not just by squamous cells from the proximal wound margin but by scattered squamous islands in which esophageal submucosal gland duct cells seem to redifferentiate into the squamous progenitors that fuel squamous re-epithelialization. SSIM can be found in most patients during the healing process. We speculate that this SSIM might underlie Barrett's recurrences after apparently successful eradication.

Endoscopic approach to eosinophilic esophagitis: American Society for Gastrointestinal Endoscopy Consensus Conference.

Endoscopy plays a critical role in caring for and evaluating the patient with eosinophilic esophagitis (EoE). Endoscopy is essential for diagnosis, assessment of response to therapy, treatment of esophageal strictures, and ongoing monitoring of patients in histologic remission. To date, less-invasive testing for identifying or grading EoE severity has not been established, whereas diagnostic endoscopy as integral to both remains the criterion standard. Therapeutic endoscopy in patients with adverse events of EoE may also be required. In particular, dilation may be essential to treat and attenuate progression of the disease in select patients to minimize further fibrosis and stricture formation. Using a modified Delphi consensus process, a group of 20 expert clinicians and investigators in EoE were assembled to provide guidance for the use of endoscopy in EoE. Through an iterative process, the group achieved consensus on 20 statements yielding comprehensive advice on tissue-sampling standards, gross assessment of disease activity, use and performance of endoscopic dilation, and monitoring of disease, despite an absence of high-quality evidence. Key areas of controversy were identified when discussions yielded an inability to reach agreement on the merit of a statement. We expect that with ongoing research, higher-quality evidence will be obtained to enable creation of a guideline for these issues. We further anticipate that forthcoming expert-generated and agreed-on statements will provide valuable practice advice on the role and use of endoscopy in patients with EoE.

Classifying Esophageal Motility by FLIP Panometry: A Study of 722 Subjects With Manometry.

INTRODUCTION: Functional luminal imaging probe (FLIP) panometry can evaluate esophageal motility in response to sustained esophageal distension at the time of sedated endoscopy. This study aimed to describe a classification of esophageal motility using FLIP panometry and evaluate it against high-resolution manometry (HRM) and Chicago Classification v4.0 (CCv4.0). METHODS: Five hundred thirty-nine adult patients who completed FLIP and HRM with a conclusive CCv4.0 diagnosis were included in the primary analysis. Thirty-five asymptomatic volunteers ("controls") and 148 patients with an inconclusive CCv4.0 diagnosis or systemic sclerosis were also described. Esophagogastric junction (EGJ) opening and the contractile response (CR) to distension (i.e., secondary peristalsis) were evaluated with a 16-cm FLIP during sedated endoscopy and analyzed using a customized software program. HRM was classified according to CCv4.0. RESULTS: In the primary analysis, 156 patients (29%) had normal motility on FLIP panometry, defined by normal EGJ opening and a normal or borderline CR; 95% of these patients had normal motility or ineffective esophageal motility on HRM. Two hundred two patients (37%) had obstruction with weak CR, defined as reduced EGJ opening and absent CR or impaired/disordered CR, on FLIP panometry; 92% of these patients had a disorder of EGJ outflow per CCv4.0. DISCUSSION: Classifying esophageal motility in response to sustained distension with FLIP panometry parallels the swallow-associated motility evaluation provided with HRM and CCv4.0. Thus, FLIP panometry serves as a well-tolerated method that can complement, or in some cases be an alternative to HRM, for evaluating esophageal motility disorders.

Prospective development and validation of a volumetric laser endomicroscopy computer algorithm for detection of Barrett's neoplasia.

BACKGROUND AND AIMS: Volumetric laser endomicroscopy (VLE) is an advanced imaging modality used to detect Barrett's esophagus (BE) dysplasia. However, real-time interpretation of VLE scans is complex and time-consuming. Computer-aided detection (CAD) may help in the process of VLE image interpretation. Our aim was to train and validate a CAD algorithm for VLE-based detection of BE neoplasia. METHODS: The multicenter, VLE PREDICT study, prospectively enrolled 47 patients with BE. In total, 229 nondysplastic BE and 89 neoplastic (high-grade dysplasia/esophageal adenocarcinoma) targets were laser marked under VLE guidance and subsequently underwent a biopsy for histologic diagnosis. Deep convolutional neural networks were used to construct a CAD algorithm for differentiation between nondysplastic and neoplastic BE tissue. The CAD algorithm was trained on a set consisting of the first 22 patients (134 nondysplastic BE and 38 neoplastic targets) and validated on a separate test set from patients 23 to 47 (95 nondysplastic BE and 51 neoplastic targets). The performance of the algorithm was benchmarked against the performance of 10 VLE experts. RESULTS: Using the training set to construct the algorithm resulted in an accuracy of 92%, sensitivity of 95%, and specificity of 92%. When performance was assessed on the test set, accuracy, sensitivity, and specificity were 85%, 91%, and 82%, respectively. The algorithm outperformed all 10 VLE experts, who demonstrated an overall accuracy of 77%, sensitivity of 70%, and specificity of 81%. CONCLUSIONS: We developed, validated, and benchmarked a VLE CAD algorithm for detection of BE neoplasia using prospectively collected and biopsy-correlated VLE targets. The algorithm detected neoplasia with high accuracy and outperformed 10 VLE experts. (The Netherlands National Trials Registry (NTR) number: NTR 6728.).

Expert assessment on volumetric laser endomicroscopy full scans in Barrett's esophagus patients with or without high grade dysplasia or early cancer.

BACKGROUND: Volumetric laser endomicroscopy (VLE) allows for near-microscopic imaging of the superficial esophageal wall and may improve detection of early neoplasia in Barrett's esophagus (BE). Interpretation of a 6-cm long, circumferential VLE "full scan" may however be challenging for endoscopists. We aimed to evaluate the accuracy of VLE experts in correctly diagnosing VLE full scans of early neoplasia and non-dysplastic BE (NDBE). METHODS: 29 VLE full scan videos (15 neoplastic and 14 NDBE) were randomly evaluated by 12 VLE experts using a web-based module. Experts were blinded to the endoscopic BE images and histology. The 15 neoplastic cases contained a subtle endoscopically visible lesion, which on endoscopic resection showed high grade dysplasia or cancer. NDBE cases had no visible lesions and an absence of dysplasia in all biopsies. VLE videos were first scored as "neoplastic" or "NDBE." If neoplastic, assessors located the area most suspicious for neoplasia. Primary outcome was the performance of VLE experts in differentiating between non-dysplastic and neoplastic full scan videos, calculated by accuracy, sensitivity, and specificity. Secondary outcomes included correct location of neoplasia, interobserver agreement, and level of confidence. RESULTS: VLE experts correctly labelled 73 % (95 % confidence interval [CI] 67 % - 79 %) of neoplastic VLE videos. In 54 % (range 27 % - 66 %) both neoplastic diagnosis and lesion location were correct. NDBE videos were consistent with endoscopic biopsies in 52 % (95 %CI 46 % - 57 %). Interobserver agreement was fair (kappa 0.28). High level of confidence was associated with a higher rate of correct neoplastic diagnosis (81 %) and lesion location (73 %). CONCLUSIONS: Identification of subtle neoplastic lesions in VLE full scans by experts was disappointing. Future studies should focus on improving methodologies for reviewing full scans, development of refined VLE criteria for neoplasia, and computer-aided diagnosis of VLE scans.

Experience and Technique for Zenker's Diverticulum Per Oral Endoscopic Myotomy: Z-POEM.

OBJECTIVE: With the advent of minimally invasive surgery, incisionless surgery, and third-space endoscopy, the treatment for Zenker's diverticulum has also moved toward less invasive techniques METHODS: New incisionless per oral techniques can be applied for cricopharyngeal myotomy in Zenker's diverticulum. RESULTS: Five patients underwent Zenker's diverticulum per oral endoscopic myotomy (Z-POEM) without complications, minimal discomfort, and narcotic consumption, with complete resolution of their symptoms by history and Eckardt scores. CONCLUSIONS: Z-POEM is performed entirely endoscopically with very little associated pain or complication rates, with short-term follow-up having excellent functional and symptomatic results.

Barrett's Esophagus and Esophageal Carcinoma: Can Biomarkers Guide Clinical Practice?

PURPOSE OF REVIEW: Despite gastrointestinal societal recommendations for endoscopic screening and surveillance of Barrett's esophagus, the rates of esophageal adenocarcinoma continue to rise. Furthermore, this current practice is costly to patients and the medical system without clear evidence of reduction in cancer mortality. The use of biomarkers to guide screening, surveillance, and treatment strategies might alleviate some of these issues. RECENT FINDINGS: Incredible advances in biomarker identification, biomarker assays, and minimally-invasive modalities to acquire biomarkers have shown promising results. We will highlight recently published, key studies demonstrating where we are with using biomarkers for screening and surveillance in clinical practice, and what is on the horizon regarding novel non-invasive and minimally invasive methods to acquire biomarkers. Proof-of principle studies using in silico models demonstrate that biomarker-guided screening, surveillance, and therapeutic intervention strategies can be cost-effective and can reduce cancer deaths in patients with Barrett's esophagus.

Aberrant p53 Immunostaining in Barrett's Esophagus Predicts Neoplastic Progression: Systematic Review and Meta-Analyses.

Risk stratification of patients with Barrett's esophagus (BE) presently relies on the histopathologic grade of dysplasia found in esophageal biopsies, which is limited by sampling error and inter-pathologist variability. p53 immunostaining of BE biopsies has shown promise as an adjunct tool but is not recommended by American gastroenterology societies, who cite insufficient evidence of its prognostic value. We have conducted a systematic review and meta-analyses to clarify this value. We searched for studies that: (1) used immunohistochemistry to assess p53 expression in esophageal biopsies of BE patients and (2) reported subsequent neoplastic progression. We performed separate meta-analyses of case-control studies and cohort studies. We identified 14 relevant reports describing 8 case-control studies comprising 1435 patients and 7 cohort studies comprising 582 patients. In the case-control study meta-analysis of the risk of neoplasia with aberrant p53 expression, the fixed- and random-effect estimates of average effect size with aberrant p53 expression were OR 3.84, p < .001 (95% CI 2.79-5.27) and OR 5.95, p < .001 (95% CI 2.68-13.22), respectively. In the cohort study meta-analysis, the fixed- and random-effect estimates of average effect size were RR = 17.31, p < .001 (95% CI 9.35-32.08) and RR = 14.25, p < .001 (95% CI 6.76-30.02), respectively. Separate meta-analyses of case-control and cohort studies of BE patients who had baseline biopsies with p53 immunostaining revealed consistent, strong, and significant associations between aberrant p53 immunostaining and progression to high-grade dysplasia or esophageal adenocarcinoma. These findings support the use of p53 immunostaining as an adjunct to routine clinical diagnosis for dysplasia in BE patients.

Can Eosinophilic Esophagitis Cause Achalasia and Other Esophageal Motility Disorders?

Eosinophilic esophagitis (EoE), a disorder identified by its esophageal mucosal features, often is associated with esophageal motility abnormalities, which are manifestations of esophageal muscle dysfunction. Those motility abnormalities sometimes normalize with treatments that reduce esophageal eosinophilia, suggesting that eosinophils can cause reversible esophageal motility disturbances, perhaps by releasing myoactive and neuroactive eosinophil products. Although achalasia uncommonly is associated with EoE as currently defined, most achalasia patients have evidence of an abnormal accumulation of eosinophils and/or their degranulation products in the esophageal muscularis propria, a location inaccessible to routine endoscopic evaluation. Achalasia is an idiopathic condition resulting from destruction of neurons in the myenteric plexus of the esophagus, and degranulating eosinophils release toxic proteins capable of destroying those neurons, thereby causing the irreversible motility abnormalities of achalasia. This report reviews data on the association of esophageal eosinophilia with achalasia and other esophageal motility abnormalities. Based on this review, we propose that EoE, like eosinophilic gastroenteritis, might have mucosal-predominant and muscle-predominant forms with different clinical manifestations. A muscle-predominant form of EoE could underlie a variety of reversible and irreversible esophageal motility disorders, including achalasia. The concept that esophageal motility abnormalities might develop from a muscle-predominant form of EoE warrants serious consideration and further investigation.

Early increase in blood supply (EIBS) is associated with tumor risk in the Azoxymethane model of colon cancer.

BACKGROUND: The present study aimed to investigate the role of blood supply in early tumorigenesis in colorectal cancer. We leveraged the renin angiotensin system (RAS) to alter colonic blood supply and determine the effect on tumor initiation and progression. METHODS: To test the effect of blood supply on tumorigenesis, 53 male A/J mice were randomly assigned to one of three RAS modulation groups and one of two AOM treatments. The RAS modulation groups were I) water (RAS-unmodulated) as a control group, II) angiotensin-II and III) the angiotensin receptor blocker, Losartan. The mice in each group were then randomly split into either the saline control condition or the AOM-treated condition in which tumors were induced with a standard protocol of serial azoxymethane (AOM) injections. To monitor microvascular changes in the rectal mucosa during the study, we used confocal laser endomicroscopy (CLE) with FITC-Dextran for in-vivo imaging of vessels and polarization-gated spectroscopy (PGS) to quantify rectal hemoglobin concentration ([Hb]) and blood vessel radius (BVR). RESULTS: At 12 weeks post-AOM injections and before tumor formation, CLE images revealed many traditional hallmarks of angiogenesis including vessel dilation, loss of co-planarity, irregularity, and vessel sprouting in the pericryptal capillaries of the rectal mucosa in AOM-Water tumor bearing mice. PGS measurements at the same time-point showed increased rectal [Hb] and decreased BVR. At later time points, CLE images showed pronounced angiogenic features including irregular networks throughout the colon. Notably, the AOM-Losartan mice had significantly lower tumor multiplicity and did not exhibit the same angiogenic features observed with CLE, or the increase in [Hb] or decrease in BVR measured with PGS. The AOM-AngII mice did not have any significant trends. CONCLUSION: In-vivo PGS measurements of rectal colonic blood supply as well as CLE imaging revealed angiogenic disruptions to the capillary network prior to tumor formation. Losartan demonstrated an effective way to mitigate the changes to blood supply during tumorigenesis and reduce tumor multiplicity. These effects can be used in future studies to understand the early vessel changes observed.

Efficacy, Durability, and Safety of Complete Endoscopic Mucosal Resection of Barrett Esophagus: A Systematic Review and Meta-Analysis.

GOALS: To report the rate of eradication and recurrence of both neoplasia and intestinal mucosa and the rate of adverse events for complete endoscopic resection (CER) of Barrett esophagus (BE). BACKGROUND: There is limited composite data on the clinical efficacy of CER of BE with high-grade dysplasia or neoplasia. STUDY: We performed a systematic review and meta-analysis of cohort studies that reported the clinical outcome of patients with BE who underwent CER and had at least 15-month follow-up after the time of elimination of BE. Main outcome of interests were pooled estimated rates of complete eradication of intestinal metaplasia and neoplasia, recurrence of intestinal metaplasia and neoplasia, and incidence of esophageal stricture, bleeding, and perforation. RESULTS: We identified 8 studies reporting on 676 patients (high-grade dysplasia 54%) that met our criteria. Pooled estimated rates of complete eradication of intestinal metaplasia and complete eradication of intestinal neoplasia were 85.0% [95% confidence interval (CI), 79.4%-89.2%] and 96.6% (95% CI, 94.0%-98.1%), respectively, and rates of recurrence of intestinal metaplasia and recurrence of intestinal neoplasia were 15.7% (95% CI, 8.0%-28.4%) and 5.8% (95% CI, 3.9%-8.6%), respectively. Estimated incidences of adverse events were stricture 37.4 (95% CI, 24.4%-52.6%), bleeding 7.9% (95% CI, 4.4%-13.8%) and perforation 2.3% (95% CI, 1.3%-4.1%). CONCLUSIONS: CER achieves an 85% complete eradication rate of BE with recurrent rate of neoplasia of 6%. Estimated rate of postprocedural stricture was 37.4%. On the basis of this high rate of adverse events and significant heterogeneity in the studies included, the present meta-analysis cannot endorse CER as sole therapy for BE.

Biomarkers of Barrett's Esophagus: From the Laboratory to Clinical Practice.

The currently recommended approach to managing cancer risk for patients with Barrett's esophagus is endoscopic surveillance including a biopsy protocol to sample the esophageal tissue randomly to detect dysplasia. However, there are numerous limitations in this practice that rely on the histopathological grading of dysplasia alone to make clinical decisions. The availability of in silico models demonstrating the potential cost-effectiveness of biomarker-based stratification has increased interest in finding a clinically relevant "Barrett's biomarker." The success of endoscopic eradication therapy in preventing neoplastic progression of dysplastic Barrett's esophagus has promoted the desire to stratify non-dysplastic Barrett's esophagus to those with "high risk" that may benefit from endotherapy. Furthermore, on the other end of the spectrum, there is interest in searching for a "low risk" marker that may identify those that would not likely benefit from endoscopy screening or surveillance. This review highlights recent data from the genomics (r)evolution revealing new genetic biomarkers of susceptibility to the development of Barrett's esophagus and novel pathways for its neoplastic progression, addresses the development of new modes of tissue sampling and imaging to detect early neoplasia in Barrett's esophagus, and discusses current progress in moving biomarkers from the laboratory into clinical practice in the era of precision medicine.

Development and Validation of a Classification System to Identify High-Grade Dysplasia and Esophageal Adenocarcinoma in Barrett's Esophagus Using Narrow-Band Imaging.

BACKGROUND & AIMS: Although several classification systems have been proposed for characterization of Barrett's esophagus (BE) surface patterns based on narrow-band imaging (NBI), none have been widely accepted. The Barrett's International NBI Group (BING) aimed to develop and validate an NBI classification system for identification of dysplasia and cancer in patients with BE. METHODS: The BING working group, composed of NBI experts from the United States, Europe, and Japan, met to develop a validated, consensus-driven NBI classification system for identifying dysplasia and cancer in BE. The group reviewed 60 NBI images of nondysplastic BE, high-grade dysplasia, and esophageal adenocarcinoma to characterize mucosal and vascular patterns visible by NBI; these features were used to develop the BING criteria. We then recruited adult patients undergoing surveillance or endoscopic treatment for BE at 4 institutions in the United States and Europe, obtaining high-quality NBI images and performing histologic analysis of biopsies. Experts individually reviewed 50 NBI images to validate the BING criteria, and then evaluated 120 additional NBI images (not previously viewed) to determine whether the criteria accurately predicted the histology results. RESULTS: The BING criteria identified patients with dysplasia with 85% overall accuracy, 80% sensitivity, 88% specificity, 81% positive predictive value, and 88% negative predictive value. When dysplasia was identified with a high level of confidence, these values were 92%, 91%, 93%, 89%, and 95%, respectively. The overall strength of inter-observer agreement was substantial (κ = 0.681). CONCLUSIONS: The BING working group developed a simple, internally validated system to identify dysplasia and EAC in patients with BE based on NBI results. When images are assessed with a high degree of confidence, the system can classify BE with >90% accuracy and a high level of inter-observer agreement.